JP2021003598A - Use of antistatic materials in airway for thermal aerosol condensation process - Google Patents

Abstract

To provide a drug delivery device where an antistatic material is used in an airway for drug aerosols susceptible to charging during aerosol generation.SOLUTION: A drug delivery device 40 comprises a drug layer 38 in a housing 42 surrounding a supply unit 10, and an airway 44 between an inlet 46 and an outlet 50 of a vaporized drug. A housing material forming the airway is formed from an antistatic material or antistatic coating.SELECTED DRAWING: Figure 4

Description

[0001] The present invention relates to materials used in devices for delivering aerosols by inhalation route. Specifically, the present invention relates to the use of antistatic materials in devices for producing aerosols containing effective drugs used in inhalation therapy.

[0002] Currently, there are a number of approved devices for inhalation delivery of drugs, including dry powder inhalers, nebulizers, and pressurized metered dose inhalers.
metered dose inhaler) is included. However, the aerosols produced by those devices generally contain excipients.

[0003] By rapidly vaporizing a thin film of drug into an air stream at a temperature of up to 600 ° C. within 500 ms, a high yield and high purity drug aerosol can be produced with minimal drug degradation. Condensed drug aerosols can be used for effective pulmonary delivery of drugs using inhaled medical devices. Devices and methods for vaporizing a thin film of drug deposited on a metal substrate by electrical resistance heating have been shown. A chemical-based heat package that can contain a fuel capable of performing an exothermic metal redox reaction in a closed container is used to generate a rapid thermal impulse that can vaporize a thin film to produce a high-purity aerosol. It can also be; for example, US Application No. 10 / 850,895, title "Self-Contained heating Unit and Drug-Supply Unit Employing Same", filed May 20, 2004, and US Application No. 10 / 851,883, title "Percussively". Ignited or Electrically Ignited Self-Contained Heating Unit and Drug Supply Unit Employing Same ”, filed May 20, 2004; both of which are incorporated herein by reference in their entirety. These devices and methods are suitable for use with compounds that can be deposited as physically and chemically stable solids.

[0004] Aerosols from MDI and DPI are often highly charged, which results in inconsistent aerosol emissions and can affect therapeutic efficacy. For example, Pierart et al. Found about 14% aerosol particle loss due to charging in MDI spacers. One factor that can affect drug emissions from the inhaler is the electrostatic interaction between the charged drug aerosol particles and the device components surrounding the aerosol.

U.S. Application No. 10 / 850,895, “Self-Contained heating Unit and Drug-Supply Unit Employing Same”, filed May 20, 2004 U.S Application No. 10 / 851,883, “Percussively Ignited or Electrically Ignited Self-Contained Heating Unit and Drug Supply Unit Employing Same”, filed May 20, 2004

[0005] Aspects disclosed herein are intended to overcome one or more of the problems discussed above.

[0006] The present disclosure teaches the use of antistatic agents in airways for thermal aerosol generation devices. The present disclosure teaches the use of antistatic agents for drug delivery in any drug that may be prone to charge during aerosol generation, such as Alprazolam. A number of possible aspects of the present disclosure include both antistatic airway materials and coatings for airways. The present disclosure applies a metallized airway (by coating the inner wall of the airway with a conductive metal such as stainless steel / copper / copper / stainless steel, or by applying a metal tape (eg copper) to the inner and outer walls of the airway. It teaches the use of antistatic sprays (eg, Stainless brand) in default airways, and the use of antistatic plastics (eg, Permastat or Permastat plus brand) as airway materials.

[0007] The present disclosure teaches drug aerosols formed using the thermal aerosol condensation method. One aspect of this technique involves a drug coated substrate placed inside the airway. For certain drugs, such as alprazolam, the aerosols formed tend to deposit indefinitely on the airways, resulting in reduced and inconsistent emissions. Some drugs form charged aerosols when vaporized under certain conditions. Charged aerosols can deposit on the airway due to electrostatic attraction. The present disclosure teaches the adoption of antistatic treatments for reducing aerosol charging and airway deposition.

[0008] The present disclosure teaches methods and devices for providing inhalation delivery of a drug, wherein the amount of drug aerosol released by thermal aerosol condensation with an antistatic material on the airway charges the airway. It provides a more consistent dose than the release of the drug aerosol formed by thermal aerosol condensation without protective material. The use of antistatic material significantly reduces the amount of drug aerosol deposited on the airway. The use of antistatic material reduces the charge on the aerosol. This method and device achieves drug delivery of a drug, characterized in that the drug forms a charged aerosol upon vaporization.

[0009] FIG. 1 shows a Staccato single dose device. [0010] FIG. 2 is a graph showing airway deposition and aerosol charging for Permastat, Permastat Plus, and standard airway materials. [0011] FIG. 3 is a graph showing aerosol characteristics using the Permasat airway. [0012] FIG. 4 is a schematic diagram of a drug delivery device.

[0013] As defined herein, the following terms shall have the following meanings as they are referred to throughout this specification.
[0014] The "aerodynamic diameter" of a particular particle represents the diameter of a spherical droplet with a density of 1 g / mL (water density) that has the same sedimentation rate as the particular particle.

[0015] “Aerosol” represents an aggregate of solid or liquid particles suspended in a gas.
[0016] “Mass concentration of aerosol” represents the mass of granules per unit volume of aerosol.

[0017] Antistatic materials include, but are not limited to, antistatic airway materials and coatings for airways. These antistatic materials are provided with metallized airways (by coating the inner wall of the airway with a conductive metal such as stainless steel / copper / copper / stainless steel and / or with metal tape (eg copper) on the inner and outer walls of the airway. Includes the use of antistatic sprays (eg, Stainless brand) in default airways, and / or the use of antistatic plastics (eg, Permastat or Permastat plus brand) as airway materials. Materials with antistatic properties are included in the present disclosure.

[0018] A "condensed aerosol" refers to an aerosol formed by vaporizing the composition, followed by cooling of the vapor, which causes the vapor to condense to form particles.
[0019] “Degradation index” represents a numerical value derived from the assay. The value is determined by subtracting the purity of the generated aerosol (expressed as a decimal) from 1.

[0020] “Drug” means any substance used to prevent, diagnose, alleviate, treat or cure a condition. The drug is preferably in the form suitable for hot steam delivery, such as in the form of an ester, free acid, or free base. The terms "drug", "compound", and "pharmaceutical" are used interchangeably herein. The term drug as described herein includes nicotine and nicotine meta-salicylate.

[0021] “Drug composition” refers to a composition comprising only a pure drug, a combination of two or more drugs, or a combination of one or more drugs with additional ingredients. Additional ingredients can include, for example, pharmaceutically acceptable excipients, carriers, and surfactants.

[0022] A "drug degradation product" or "pyrolysis product" is used interchangeably to mean any by-product that is produced by heating a drug (s) and does not contribute to producing a therapeutic effect. To do.

[0023] A "drug supply article" or "drug supply unit" is used interchangeably and represents a substrate on which at least a portion of its surface is coated with one or more drug compositions. The drug-supplied article of the present invention may also include additional elements, such as, but not limited to, heating elements.

[0024] The "drug degradation product fraction" is the amount of drug degradation products present in the aerosol particles divided by the amount of drug plus drug degradation products present in the aerosol, ie (in the aerosol). Sum of the amounts of all drug degradation products present) / ((amount of drug (s) present in the aerosol) + (sum of all drug degradation products present in the aerosol)) Represent. As used herein, the term "percentage of drug degradation products" refers to the drug degradation product fraction multiplied by 100%, while the "purity" of the aerosol represents 100% minus the percent drug degradation products.

[0025] A "heat-stable drug" represents a drug having a TSR ≥ 9 when vaporized from a film of 0.05 μm to 20 μm thickness.
[0026] The "Mass median aerodynamic diameter" or "MMAD" of an aerosol involves half the particle mass of the aerosol with particles with an aerodynamic diameter greater than MMAD and half with MMAD. Represents the aerodynamic diameter in which particles with smaller aerodynamic diameters are involved.

[0027] “Number concentration” represents the number of particles per unit volume of the aerosol.
[0028] As used herein with respect to aerosol purity, "purity" means a drug composition fraction in an aerosol / a drug composition fraction in an aerosol plus a drug degradation product. Therefore, the purity is relative considering the purity of the starting material. For example, if the starting drug or starting drug composition used in the substrate coating contained detectable impurities, the reported aerosol purity is free of impurities that are present in the starting material and also found in the aerosol; for example. In certain cases, if the starting material is found to contain 1% impurities and the aerosol is found to contain the same 1% impurities, then the purity of the aerosol will nevertheless be a detectable 1% impurity. Can be reported as> 99% purity, reflecting the fact that it was not produced by the vaporization-condensation aerosol generation process.

[0029] “Settlement velocity” represents the final velocity of aerosol particles that are gravitationally settling in air.
[0030] “Support” refers to a material on which the composition is generally adhered as a coating or thin film. The terms "support" and "substrate" are used interchangeably herein.
“Substantially free of” means that the substances, compounds, aerosols, etc. described are at least 95% free of other components that are substantially free.

[0032] The “general patient tidal volume” represents 1 L for adults and 15 mL / kg for pediatric patients.
[0033] “Therapeutic effective amount” means the amount required to achieve a therapeutic effect. The therapeutic effect may be any therapeutic effect ranging from prevention, symptom improvement, symptom treatment to termination or cure of the disease.

[0034] A “Thermal stability ratio” or “TSR” has a purity of <99.
.. If it is 9%, it means purity% / (100% -purity%), and if the purity% is ≧ 99.9%, it means 1000. For example, a respiratory drug that vaporizes at 90% purity would have a TSR of 9.

[0035] A "4 μm thermostable ratio" or "4TSR" heats a drug-containing membrane of about 4 microns under conditions sufficient to vaporize at least 50% of the drug in the membrane and collects the resulting aerosol. , Means the TSR of a drug, determined by determining the purity of the aerosol and using that purity to calculate the TSR. For such vaporization, a drug membrane generally about 4 micron thick is heated to about 350 ° C. (but not below 200 ° C.) for about 1 second to vaporize at least 50% of the drug in the membrane.

[0036] A “1.5 μm aerosol” or “1.5 TSR” heats a drug-containing membrane of about 1.5 microns under conditions sufficient to vaporize at least 50% of the drug in the membrane. It means the TSR of a drug, which is determined by collecting the resulting aerosol, determining the purity of the aerosol, and using that purity to calculate the TSR. During such vaporization, a drug membrane generally about 1.5 micron thick is heated to about 350 ° C. (but not below 200 ° C.) for about 1 second to vaporize at least 50% of the drug in the membrane. ..

A “0.5 μm aerosol” or “0.5 TSR” heats a drug-containing membrane of about 0.5 micron under conditions sufficient to vaporize at least 50% of the drug in the membrane. It means the TSR of a drug, which is determined by collecting the resulting aerosol, determining the purity of the aerosol, and using that purity to calculate the TSR. During such vaporization, a drug membrane generally about 0.5 micron thick is heated to about 350 ° C. (but not below 200 ° C.) for about 1 second to vaporize at least 50% of the drug in the membrane. ..

[0038] “Vapor” represents a gas and “steam phase” represents a gas phase. The term "hot steam" preferably refers to a steam phase, aerosol, or aerosol-steam mixture formed by heating.

[0039] When a condensed aerosol is formed in the air stream, a percentage of the aerosol deposits on the downstream physical product, such as the side wall of the airway that defines the air flow, the mouthpiece of the device, or other structure. , Which can reduce the amount of effective compound released by the device and used for administration. For many treatment plans, the ability to deliver doses containing accurate, consistent and reproducible amounts of bioactive compounds affects the therapeutic efficacy of the treatment plan, and in some cases such ability is new. May enable therapy. Thus, there is a need for inhalation devices and methods that produce condensed aerosols capable of delivering accurate and reproducible and / or controlled amounts of bioactive material. The present disclosure teaches the use of antistatic agents in airways for thermal aerosol generators. The present disclosure teaches the use of antistatic materials for drug delivery in any drug that may be prone to charge during aerosol generation, such as alprazolam. Many possible aspects of the present disclosure include both antistatic airway materials and coatings for airways. The present disclosure is manufactured by metallized airways (by coating the inner wall of the airway with a conductive metal such as stainless steel / copper / copper / stainless steel, or by applying metal tape (eg copper) to the inner and outer walls of the airway. (E.g.), the use of antistatic sprays (eg, Stainless brand) in default airways, and the use of antistatic plastics (eg, Permastat or Permastat plus brand) as airway materials.

Aerosol composition
[0040] The compositions described herein generally include pharmaceutical compounds. The composition can also include other compounds. For example, the composition can include a mixture of a pharmaceutical compound and a pharmaceutically acceptable excipient, or a mixture of a pharmaceutical compound and other compounds having useful or desirable properties. The composition can also include pure pharmaceutical compounds. In one embodiment, the composition consists essentially of pure drug and is free of propellants or solvents.

[0041] Further, pharmaceutically acceptable carriers, surfactants, enhancers, and inorganic compounds may be included in the composition. Examples of such substances are known in the art.
[0042] In some variations, the aerosol is substantially free of organic solvents and propellants. In addition, water is not added as a solvent for nicotine meta-salicylate, but water from the atmosphere can be taken up by the aerosol being formed, especially while the air stream passes over the membrane and during the cooling process. There is. In other variations, the aerosol is completely free of organic solvents and propellants. In yet another variation, the aerosol is completely free of organic solvents, propellants, and any excipients. These aerosols contain only pure drugs, less than 10% drug degradation products, and carrier gases (generally air).

[0043] In general, drugs have a degradation index of less than 0.15. Preferably, the drug has a degradation index of less than 0.10. More preferably, the drug has a degradation index of less than 0.05. Most preferably, the drug has a degradation index of less than 0.025.

[0044] In one variation, the condensed aerosol comprises at least 5% by weight of condensed drug aerosol particles. In other variations, the aerosol comprises at least 10%, 20%, 30%, 40%, 50%, 60%, or 75% by weight of condensed drug aerosol particles. In yet other variations, aerosols are at least 95%, 99%
, Or 99.5% by weight of condensed drug aerosol particles.

[0045] In one variation, the condensed aerosol particles contain less than 10% by weight of pyrolysis products. In other variations, condensed drug aerosol particles contain less than 5%, 1%, 0.5%, 0.1%, or 0.03% by weight pyrolysis products.

[0046] In certain aspects of the disclosure, the drug aerosol is 90% -99.8%, or 93% -99.7%, or 95% -99.5%, or 96.5% -99.2%. Has the purity of. In certain aspects of the disclosure, the drug aerosol is 90% -99.8%, or 93% -99.7%, or 95% -99.5%, or 96.5% -99.2%, in the aerosol. Has a free base nicotine percent.

[0047] In general, the aerosol has a larger number concentration particles ¹⁰⁶ / mL. In other variations, the aerosol has a larger number concentration 10 ⁷ cells / mL. In yet another variation, the aerosol has greater than 10 ⁸ cells / mL, greater than 10 ⁹ cells / mL, greater than ^{10 10} cells / mL, or ^{10 11} cells / mL greater number concentration.

[0048] The gas of an aerosol is generally air. However, other gases, especially inert gases such as argon, nitrogen, helium, etc. can be used. The gas can also include vapors of compositions that have not yet condensed to form particles. In general, the gas does not contain propellants or vaporized organic solvents. In one variation, the condensed aerosol comprises at least 5% by weight of condensed drug aerosol particles. In other variations, the aerosol comprises at least 10%, 20%, 30%, 40%, 50%, 60%, or 75% by weight of condensed drug aerosol particles. In yet another variation, the aerosol comprises at least 95%, 99%, or 99.5% by weight condensed aerosol particles.

[0049] In one variation, the condensed drug aerosol has an MMAD in the range of about 0.01-3 μm. In one variation, the condensed drug aerosol has an MMAD in the range of about 0.1 to 3 μm. In one variation, the MMAD-centric geometric standard deviation of condensed drug aerosol particles is less than 3.0. In other variations, the MMAD-centric geometric standard deviation of condensed drug aerosol particles is less than 2.5, or less than 2.0.

[0050] In certain aspects of the invention, the drug aerosol comprises one or more drugs having at least 5 or 10 4 TSRs, at least 7 or 14 1.5 TSRs, or at least 9 or 18 0.5 TSRs. In another aspect of the invention, the drug aerosol is one or more having 4 TSRs of 5 to 100 or 10 to 50, 1.5 TSRs of 7 to 200 or 14 to 100, or 0.5 TSRs of 9 to 900 or 18 to 300. Includes drugs.

Formation of condensed aerosol
Any suitable method can be used to form the condensed aerosols described herein. One such method involves heating the composition to form a vapor, followed by cooling the vapor so that it forms an aerosol (ie, a condensed aerosol). The method is described earlier in US. Patent No. 7,090,830. The entire reference is incorporated herein by reference.
[0052] Generally, the composition is coated on a substrate and then the substrate is heated to vaporize the composition. The substrate may have any geometric shape and may be of a wide variety of sizes. Substrate has a large surface area-to-volume ratio (eg, greater than 100 per meter)
And it is often desirable to have a large surface area-to-mass ratio (eg, greater than 1 cm ² per gram). The substrate can have more than one surface.

[0053] It is also possible to convert a substrate of one shape into another shape having different properties. For example, a flat sheet with a thickness of 0.25 mm has a surface area-to-volume ratio of approximately 8,000 per meter. Rolling this sheet into a hollow cylinder with a diameter of 1 cm produces a support with a higher surface area-to-mass ratio than the original sheet but a lower surface area-to-volume ratio (about 400 per meter).

[0054] A substrate can be constructed using a wide variety of materials. In general, the substrate is thermally conductive and includes metals such as aluminum, iron, copper, stainless steel, alloys, ceramics, and filled polymers. In one variation, the substrate is stainless steel. Material combinations and coated forms can also be used.

[0055] If it is desirable to use aluminum as the substrate, aluminum foil is a suitable material. Examples of alumina and silicon-based materials are BCR171 (alumina with a defined surface area greater than 2 m ² / g, from Aldrich, St. Louis, Missouri) and silicon wafers used in the semiconductor industry.

[0056] In general, it is desirable that the surface irregularities of the substrate are relatively small or substantially nonexistent. A variety of supports can be used, but supports with impermeable surfaces or impermeable surface coatings are generally preferred. Specific examples of such supports include metal foils, smooth metal surfaces, non-porous ceramics and the like. Instead of or in addition to the preferred substrate having an impermeable surface, the substrate surface area is characterized by a continuous surface area of about 20 mm ² . Instead of or in addition to the preferred substrate having an impermeable surface, the substrate surface area is a continuous surface area greater than about 1 mm ² , preferably greater than 10 mm ² , more preferably 50 mm ² , even more preferably greater than 100 mm ^2. , And a material density greater than 0.5 g / cc. In contrast, unfavorable substrates generally have a substrate density of less than 0.5 g / cc (eg, threads, felts and foams) or a surface area of less than 1 mm ² / particle (eg, small alumina particles). , And other inorganic particles); because it is difficult to generate therapeutic doses of drug aerosols by vaporization with less than 10% drug degradation on these types of surfaces.

[0057] In one variation, the present disclosure teaches a stainless steel foil substrate. A hollow stainless steel pipe can be used as a drug membrane base material. In other variations, the aluminum foil can be used as a substrate for the test drug.

[0058] The composition is generally coated on a solid support in the form of a film. The membrane can be coated on the solid support using any suitable method. The appropriate method for coating often depends on the physical properties of the compound and the desired film thickness. An example of a method of coating a composition on a solid support is to prepare a solution of the compound (alone or in combination with other desirable compounds) in a suitable solvent and apply the solution to the outer surface of the solid support. Then by removing the solvent (eg, by evaporation, etc.), thereby leaving the film on the surface of the support.

[0059] Common solvents include methanol, dichloromethane, methyl ethyl ketone, diethyl ether, acetone, ethanol, isopropyl alcohol, 3: 1 chloroform: methanol mixture, 1: 1 dichloromethane: methyl ethyl ketone mixture, dimethylformamide, and deionized water. Is done. In some cases (eg, when using triamterene), it is desirable to use a solvent such as formic acid. If desired, sonication can also be used to dissolve the compound.

The composition can also be coated on the solid support by immersing the support in the composition solution, or by spraying, brushing, or otherwise applying the solution to the support. .. Alternatively, a melt of the drug can be prepared and applied to the support. For drugs that are liquid at room temperature, the thickener is mixed with the drug to allow the application of a solid drug membrane.

The thickness of the membrane can be varied depending on the compound and the desired maximum pyrolysis amount. In one method, heating the composition involves heating a thin composition film having a thickness of about 0.1 μm to 30 μm to form vapor. In yet other variations, the composition has a film thickness of about 0.5 μm to 21 μm. Most commonly, the film thickness to be vaporized is 0.5 μm to 25 μm.

[0062] The support coated with the film of the composition can be heated by various means to vaporize the composition. Typical heating methods include energizing electrical resistance elements, absorbing electromagnetic waves (eg microwaves or laser beams), and exothermic chemical reactions (eg exothermic solvation, hydration of pyrophoric substances). And oxidation of flammable substances). Substrate heating by conductive heating is also appropriate. One of the representative heat sources is described in the US patent application, SELF-CONTAINED HEATING UNIT AND DRUG-SUPPLY UNIT EMPLOYING SAME, USSN 60/472,697, May 21, 2003 application. The description of typical heat sources disclosed herein is incorporated herein by reference.

[0063] The heat source generally achieves a substrate temperature of at least 200 ° C., preferably at least 250 ° C., or more preferably at least 300 ° C. or 350 ° C. within 2 seconds, preferably within 1 second, or more preferably. Heat is supplied to the substrate at a rate that substantially completely volatilizes the drug composition from the substrate within 0.5 seconds. Suitable heat sources include resistance heating devices, such as at least 200 ° C, 250 ° C, 300 ° C, or 350 ° C substrate temperatures, preferably within 50-500 ms, more preferably 50-200 ms. Current is supplied to it at a rate sufficient to achieve rapid heating within the range. For example, a heat source or device containing a chemically reactive substance that undergoes an exothermic reaction when actuated by a spark or heating element, such as a flush valve type heater of the type described in some examples, and the US patent application, SELF- cited above. The heat source described in CONTAINED HEATING UNIT AND DRUG-SUPPLY UNIT EMPLOYING SAME is also appropriate. In particular, assuming that the thermal coupling between the heat source and the substrate is good, heat is generated by an exothermic reaction in which the chemical "loading" of the heat source is consumed in a period of 50 to 500 ms or less. The heat source generated is generally appropriate.

[0064] When heating a thin film of a composition, it is desirable for the vaporized compound to move rapidly from the heated surface or surrounding heated gas to a cooler environment to avoid decomposition. This can be achieved not only by rapid heating of the substrate, but also by the use of a gas stream across the surface of the substrate. Although vaporized vapors from the surface can move due to Brownian motion or diffusion, the time of this movement is a range of elevated areas of surface temperature established by the velocity gradient of the gas on the surface and the physical shape of the surface. May be affected by. Typical gas flow rates used to minimize such degradation and generate the desired particle size are 1-10 L / min.

[0065] Aerosol particles for administration are generally by using the method of any of it can be formed at a rate greater than the respirable particles 10 ⁸ / sec. In some variations, the aerosol particles for administration is formed at a rate greater than the respirable particles 10 ⁹ or 10 ¹⁰ / sec. Similarly, with respect to aerosol formation (ie, the mass of aerosolized granules produced by the delivery device per unit time), 0.5 m, greater than 0.25 mg / sec.
Aerosols can be formed at rates greater than g / sec or greater than 1 or 2 mg / sec. Furthermore, with respect to aerosol formation, the rate of drug aerosol formation (ie, the proportion of pharmaceutical compounds released in aerosol form by the delivery device per unit time) is greater than 0.05 mg / sec for drug, greater than 0.1 mg / sec for drug. The drug can be aerosolized at a rate greater than 0.5 mg / sec of drug, or greater than 1 or 2 mg / sec of drug.

[0066] In one variation, the drug-condensed aerosol is formed from a composition that supplies at least 5% by weight of the drug-condensed aerosol particles. In other variations, the aerosol is formed from a composition that supplies at least 10%, 20%, 30%, 40%, 50%, 60%, or 75% by weight drug condensed aerosol particles. In yet another variation, the aerosol is formed from a composition that supplies at least 95%, 99%, or 99.5% by weight of drug condensed aerosol particles.

[0067] In one variation, the drug-condensed aerosol particles contain less than 10% by weight of pyrolysis products at the time of formation. In other variations, the drug condensed aerosol particles contain less than 5%, 1%, 0.5%, 0.1%, or 0.03% by weight of pyrolysis products at the time of formation.

[0068] In one variation, the drug condensed aerosol is produced in the gas stream at a rate at which the produced aerosol has an MMAD in the range of about 0.1 to 3 μm. In one variation, the MMAD-centered geometric standard deviation of the drug-condensed aerosol particles is less than 3.0. In other variations, the MMAD-centric geometric standard deviation of the drug-condensed aerosol particles is less than 2.5, or less than 2.0.

Delivery device
[0069] A delivery device for administration of a condensed drug aerosol as described herein generally comprises an element for heating the composition to form a vapor and an element for cooling the vapor thereby forming a condensed aerosol. Including. These aerosols are generally delivered by inhalation to the patient's lungs for local or systemic treatment. However, the drug-aerosol particles can be applied to the target site or the condensed aerosols of the invention can be generated in the air stream. For example, an air stream carrying drug-aerosol particles can be applied to treat acute or chronic skin conditions, can be applied to the incision site during a surgical procedure, or can be applied to open wounds. .. This delivery device can be combined with a composition containing a unit dosage form of the drug for use as a kit.

[0070] The devices described herein can further include a variety of components to facilitate aerosol delivery. For example, the device can include any component known in the art for controlling the timing of drug aerosolization for inhalation (eg, inspiratory actuation). Similarly, the device can include a component to provide feedback to the patient on the rate and / or volume of inhalation, or a component to prevent overuse (ie, a "lockout" crop). The device can further include crops such as weighing / logging or tapering schemes. In addition, the device can further include a component for blocking use by an unauthorized individual and a component for recording the dosing history. These components can be used alone or in combination with other components.

[0071] The element to be cooled may have any structure. For example, it may be an inert passage connecting the heating means to the inhalation means. Similarly, the element that allows inhalation by the user may have any structure. For example, it may be an exit portal that forms a connection between the cooling element and the user's respiratory system.

[0072] The present disclosure teaches the Staccato device shown in FIG. 4 using an antistatic material for the airway.
[0073] Antistatic materials include, but are not limited to, both antistatic airway materials and coatings for airways. The present disclosure is manufactured by metallized airways (by coating the inner wall of the airway with a conductive metal such as stainless steel / copper / copper / stainless steel, or by applying metal tape (eg copper) to the inner and outer walls of the airway. (E.g.), the use of antistatic sprays (eg, Stainless brand) in default airways, and the use of antistatic plastics (eg, Permastat or Permastat plus brand) as airway materials.

[0074] Generally, the drug delivery article is heated to a temperature sufficient to vaporize all or part of the membrane, whereby the composition forms a vapor, which is loaded into the air stream upon inhalation. As mentioned above, heating of the drug feed article can be achieved using, for example, an electrical resistance wire embedded or inserted in a substrate and connected to a battery placed in a housing. Heating can be activated, for example, with a button on the housing or by inspiratory actuation, as is known in the art.

[0075] Other devices that can be used to form and deliver the aerosols described herein are: The device includes an element for heating the composition to form a vapor, an element for cooling the vapor and thereby forming a condensed aerosol, and an element allowing the user to inhale the aerosol. The device also includes an upper outer housing member and a lower outer housing member that fit together.

[0076] The downstream end of each housing member is gently tapered for insertion into the user's mouth. The upstream ends of the upper and lower housing members have slots for taking in air when inhaled by the user (slots on one or both). The upper and lower housing members define the chamber when fitted together. A drug supply unit is placed in the chamber.

[0077] The solid support may have any desired structure. At least part of the surface of the substrate is coated with a composition film. For the example of a thermite-type heat source, the inner region of the substrate contains a suitable substance to generate heat. The substance may be a solid chemical fuel, a chemical that generates heat when mixed, an electric resistance wire, or the like. The end piece can contain the power supply, if necessary for heating, and any valve device required for the suction device. The power source may be a piece that mates with the drug supply unit.

[0078] In one variation of the device used, the device comprises a drug composition delivery article composed of: substrate, film of selected drug composition on substrate surface, and temperature above 200 ° C. In or in other embodiments, the substrate is heated to a temperature above 250 ° C., 300 ° C. or 350 ° C. at a rate effective to substantially completely volatilize the drug composition within a period of less than 2 seconds. A heat source for supplying heat to the substrate.

Other drug-supplied articles that can be used in combination with the device are described herein. Various coating methods are known in the art and / or described above.

[0080] FIG. 4 is a schematic diagram of the drug delivery device 40. The drug delivery device 40 includes a housing 42 that surrounds the drug supply unit 10, which defines an airway 44. During use, air can be drawn into the housing 42 via the airway 44 by sucking air into the outlet 50 in the direction of arrow 48 through the inlet 46. Upon use, the drug layer 38 is vaporized and the vaporized drug is entrained in the air and then condensed in the condensing space 52 to form an aerosol, whereby the condensed aerosol can be delivered through the outlet 50. The drug delivery device can be of a structure and size that provides the air flow rate required to form aerosol particles of selected size from a variety of drugs.

[0081] The airway housing material can be made of antistatic material. Many possible embodiments of the present disclosure include both antistatic airway materials and coatings for airways. The present disclosure is manufactured by metallized airways (by coating the inner wall of the airway with a conductive metal such as stainless steel / copper / copper / stainless steel, or by applying metal tape (eg copper) to the inner and outer walls of the airway. (E.g.), the use of antistatic sprays (eg, Stainless brand) in default airways, and the use of antistatic plastics (eg, Permastat or Permastat plus brand) as airway materials.

An example of a heating element has been shown as an electrical resistance wire that generates heat when an electric current flows through it, but as pointed out above, a wide variety of heating methods and corresponding devices are acceptable. For example, an acceptable heat source can supply heat to the drug feed article at a rate that quickly reaches a temperature sufficient to completely vaporize the composition from the surface of the support. For example, a heat source that achieves a temperature of 200 ° C. to 500 ° C. or higher within a period of 2 seconds is common; it should be recognized that the temperature chosen depends on the vaporization properties of the composition, but in general. It is heated to a temperature of at least about 200 ° C., preferably at least about 250 ° C., more preferably at least about 300 ° C. or 350 ° C. Heating the substrate produces a drug composition vapor, which in the presence of a fluid gas produces aerosol particles in the desired size range. The presence of the gas stream is generally before, at the same time as, or after heating the substrate. In one embodiment, the substrate is heated for a period of less than about 1 second, more preferably less than about 500 ms, even more preferably less than about 200 ms. Drug-aerosol particles are inhaled by the subject for delivery to the lungs.

[0083] The device can also include a gas flow control valve located upstream of the solid support to limit the gas flow rate through the condensing region. The gas flow valve can include, for example, an inlet that communicates with the chamber, and a deformable flap that is adapted to divert or limit the air flow gradually away from the inlet as the pressure increases beyond the valve. .. Similarly, the gas flow valve can include an actuation switch. In this variation, the movement of the valve will respond to the air pressure difference before and after the valve, which could function, for example, to close the switch. The gas flow valve can also include an opening designed to limit the air flow rate into the chamber.

[0084] The device may also include a bypass valve that communicates with the chamber downstream of the unit to offset the airflow reduction caused by the gasflow control valve as the user draws air into the chamber. In this way, the bypass valve can work with the gas control valve to control the flow through the condensing region of the chamber and the total amount of air drawn into the device. Therefore, in this variation, the total volume of air flow through the device would be the sum of the air volume flow velocity through the gas control valve and the air volume flow velocity through the bypass valve.

[0085] The gas control valve can function, for example, to limit the air drawn into the device to a preselected level, such as 15 L / min. In this way, the air flow for producing particles of the desired size can be preselected and generated. For example, when this selected airflow level is reached, additional air drawn into the device causes a pressure drop on the side beyond the bypass valve, which in turn passes through the bypass valve and downstream of the device adjacent to the user's mouth. It will contain the airflow entering the end. Thus, the user feels that the two valves distribute the total airflow to the desired air flow velocity and the bypass air flow velocity, and all the intake air is drawn in.

[0086] These valves can be used to control the rate of gas passing through the condensing region of the chamber and thus the particle size of the aerosol particles produced. In general, the faster the air flow, the smaller the particles. Thus, the gas velocity through the condensing region of the chamber can be altered by modifying the gas flow control valve to increase or decrease the air volume flow velocity in order to obtain smaller or larger particles. For example, a chamber with a substantially smooth surface wall would have a selected gas flow rate in the range of 1-10 L / min to produce condensed particles in the size range of about 1-3.5 μm MMAD. ..

[0087] Further, as is obvious to those skilled in the art, by modifying the cross section of the chamber condensing region to increase or decrease the gas ray velocity in order to obtain a specific volumetric flow velocity, and / or generate turbulence in the chamber The particle size can be changed depending on the presence or absence of the structure to be made. Thus, for example, in order to generate condensed particles in the size range of 10 to 100 nm MMAD, the chamber can be equipped with a gas flow barrier to generate air turbulence in the condensed chamber. These barriers are generally located within a few thousandths of an inch from the surface of the substrate.

Drug composition film thickness
[0088] Generally, the drug composition membrane coated on the solid support has a thickness of about 0.05-30 μm, generally 0.1-30 μm. More generally, the thickness is about 0.2-30 μm; more generally, the thickness is about 0.5-30 μm, and most commonly the thickness is about 0.5-25 μm. is there. The desired film thickness for any particular drug composition is generally determined by iterative methods, in which the desired yield and purity of the condensed aerosol composition is selected or known.

[0089] For example, if the purity of the particles is lower than desired, or if the yield is lower than desired, the thickness of the drug membrane is adjusted to a thickness different from the initial film thickness. Purity and yield are then determined for the prepared film thickness and this process is repeated until the desired purity and yield are achieved. After selecting the appropriate film thickness, determine the substrate area required to supply the therapeutically effective amount.

[0090] Generally, the film thickness for a particular drug composition is such that the drug-aerosol particles formed by vaporizing the drug composition by heating the substrate and loading the vapor into a gas stream ( i) 10% by weight or less, more preferably 5% by weight or less, most preferably 2.5% by weight or less of the drug decomposition product, and (ii) at least 50% of the total amount of the drug composition contained in the membrane. It includes. The area of the substrate on which the drug composition membrane is formed is selected so that an effective amount of drug aerosol for human therapy is achieved, as further described below.

[0091] One method that can be used to determine the thickness of the drug membrane is to determine the area of the substrate and calculate the thickness of the drug membrane using the following relational expression:
Film thickness (cm) = drug mass (g) / [drug density (g / cm ³ ) x substrate area (cm ² )]
[0092] The drug mass can be determined by weighing the substrate before and after drug membrane formation, or by extracting the drug and analyzing and measuring the amount. Drug densities can be determined experimentally by a variety of techniques, are known to those of skill in the art, or can be found in the literature or in reference texts, such as in CRC. If the actual drug density is not known, it is acceptable to estimate the unit density.

A substrate with a drug membrane of known thickness was heated to a temperature sufficient to generate hot steam. All or part of the hot vapor is recovered and analyzed for the presence of drug degradation products to determine the purity of the aerosol particles in the hot vapor. There is a clear relationship between the film thickness and the purity of the aerosol particles, and the purity increases while the film thickness decreases.

[0094] In addition to selecting the thickness of the drug membrane that supplies the aerosol particles containing 10% or less drug degradation products (ie, aerosol particles with a purity of 90% or higher), the temperature sufficient to vaporize the membrane. The film thickness is selected so that at least about 50% of the total amount of the drug composition contained in the membrane is vaporized when the substrate is heated.

[0095] To obtain higher purity aerosols, a smaller amount of drug can be coated to heat a thinner membrane, or the same amount of drug but with a larger surface area can be used. In general, as discussed above, impurities linearly decrease with a linear film thickness reduction, except for drug membranes of extremely thin thickness.

Thus, for drug compositions in which aerosols exhibit increased levels of drug degradation products, especially at thicknesses greater than 0.05-30 microns, with increasing film thickness, particle aerosols with less than 5% drug degradation. The film thickness on the substrate that can be formed will generally be 0.05-30 microns, for example the maximum or near maximum thickness in this range.

[0097] Another method produces drug-aerosol particles with the desired level of drug composition purity by forming hot vapors in a controlled atmosphere of an inert gas such as argon, nitrogen, helium. Consider.

[0098] The substrate required to supply a therapeutically effective amount once the desired purity and yield have been achieved, or when the corresponding film thickness can be determined by estimating from the aerosol purity-vs-film thickness graph. The area is determined.

Base material area
[0099] As pointed out above, the surface area of the substrate surface area is selected to be sufficient to obtain a therapeutically effective amount. The amount of drug that supplies the therapeutic amount is generally known in the art and will be discussed further below. The required amount and selected film thickness considered above dominate the minimum required substrate area according to the following relational expression:
Film thickness (cm) x drug density (g / cm ³ ) x substrate area (cm ² ) = dose (g)
That is, base material area (cm ² ) = dose (g) / [thickness (cm) x drug density (g / cm ³ )]
[00100] The drug mass can be determined by weighing the substrate before and after drug membrane formation, or by extracting the drug and analyzing and measuring the amount. Drug densities can be determined experimentally by a variety of well-known techniques or can be found in the literature or in reference texts, such as in CRC. If the actual drug density is not known, it is acceptable to estimate the unit density.

[00101] A therapeutic amount of drug aerosol will be obtained for a selected film thickness to produce a drug feed article consisting of a drug membrane on a thermally conductive substrate that can be administered in an effective amount for human therapy. The minimum substrate surface area is determined using the above relational expression for determining the substrate area.

[00102] In one variation, the selected substrate surface area is approximately 0.05-500c.
It is m ² . In other cases, the surface area is about 0.05-300 cm ² . In one embodiment, the surface area of the substrate is 0.05 to 0.5 cm ² . In one embodiment, the surface area of the substrate is 0.1 to 0.
.. It is 2 cm ² . The actual amount of drug delivered from the drug supply article, i.e. yield or release rate, will depend on the percentage of drug membrane that vaporizes when the substrate is heated, along with other factors. Thus, for drug membranes that yield 100% drug membranes and aerosol particles with 100% drug purity when heated, the dose, thickness and area relationships listed above are directly correlated with the dose supplied to the user. To do. As the yield and / or particle purity decreases, the substrate area can be adjusted as needed to provide the desired dose. As will be appreciated by those skilled in the art, a substrate area greater than the maximum area calculated for a particular film thickness can also be used to deliver a therapeutically effective amount of the drug. Moreover, as will be appreciated by those skilled in the art, the membrane does not need to coat the entire tablespace if the selected surface area exceeds the minimum required to deliver the therapeutic dose from the selected film thickness.

Dosage of drug-containing aerosol
[00103] The amount of drug delivered in the aerosol is such that the drug is heated under specified conditions.
It represents the unit amount obtained by cooling the resulting vapor and delivering the resulting aerosol. A "unit amount" is the total amount of drug in a particular volume of inhaled aerosol. The unit amount can be determined by collecting the aerosol, analyzing its composition according to the description herein, and comparing the results of the analysis of the aerosol with that of a series of standards containing known amounts of the drug. The amount of drug or drug required in the starting composition for delivery as aerosol is the amount of drug or drug that enters the hot vapor phase when heated (ie, the amount produced by the starting drug or drug). It depends on the bioavailability of the aerosol drug or drug, the inhalation volume of the patient, and the titer of the aerosol drug or drug as a function of plasma drug concentration.

[00104] The dose of drug-containing aerosol suitable for treating a particular condition can be determined using methods such as animal studies and dose-finding (Phase I / II) clinical trials. These experiments can also be used to assess the potential pulmonary toxicity of aerosols. Some animal studies involve measuring plasma drug concentrations in animals after exposure to aerosols. Mammals, such as dogs or primates, are commonly used for such tests because their respiratory system is similar to that of humans and the test results are generally properly extrapolated to humans. The initial dose level for testing in humans is generally less than or equal to the dose that produced the plasma drug level associated with the therapeutic effect in humans in a mammalian model. Dose escalation is then performed in humans until an optimal therapeutic response is obtained or dose limiting toxicity is observed. The actual effective drug amount for a particular patient is the specific drug or combination thereof, the particular composition in which it is formulated, the mode of administration, and the patient's age, weight and condition, and the episode being treated. May vary depending on severity.

Particle size
[00105] Effective aerosol delivery to the lungs requires the particles to have constant permeation and sedimentation or diffusion properties. Deposits in the deep lungs are caused by gravitational sedimentation, and it is necessary for the particles to have an effective sedimentation size of generally 1-3.5 μm, which is defined as the aerodynamic mass median diameter (MMAD). For smaller particles, deposition in the deep lung is caused by a diffusion process, which requires a particle size in the range of 10-100 nm, generally 20-100 nm. Inhaled drug delivery devices for deep lung delivery should produce an aerosol containing particles of one of these two size ranges, preferably about 0.1 to 3 μm MMAD. Generally, a gas or air is passed over a solid support at a specific flow rate to produce particles with the desired MMAD.

[00106] During the condensation phase, the MMAD of the aerosol increases over time. Generally, in variations of the invention, the MMAD increases in the size range of 0.01 to 3 microns as the vapor aggregates as it cools by contact with the carrier gas, followed by the aerosol particles with each other. It grows further as it collides and aggregates into larger particles. Most commonly, MMAD grows from <0.5 micron to> 1 micron within 1 second. Thus, in general, immediately after condensing into particles, the MMAD of the condensed aerosol doubles at least once per second, often at least 2, 4, 8 or 20 times per second. In other variations, MMAD increases within the size range of 0.1 to 3 microns.

[00107] In general, the higher the flow velocity, the smaller the particles formed. Therefore, the flow velocity through the condensing region of the delivery device can be varied to obtain smaller or larger particles. Particle size desired, a ratio of particle size number concentration of the mixture wishes upon approximately reached particles 10 ⁹ cells / mL can be achieved by mixing a volume with a compound in the vapor state to the carrier gas Achieved. Particle growth at this number concentration is then slow enough to be considered "stable" in particle size for a single deep inhalation. This can be done, for example, by modifying the gas flow control valve to increase or decrease the air volume flow velocity. Specifically, by selecting the gas flow rate on the vaporizing drug to be in the range of 1-10 L / min, preferably in the range of 2-8 L / min, the size range is 0.1 to 3 μm MMAD. Condensed particles can be generated.

[00108] Further, as those skilled in the art recognize, the particle size can also be varied by modifying the cross section of the chamber condensing region to increase or decrease the linear velocity of the gas for a particular volumetric flow velocity. In addition, the particle size can be changed by the presence or absence of structures that create turbulence in the chamber. Thus, for example, in order to generate condensed particles in the size range 10-100 nm MMAD, the chamber may be provided with a gas flow barrier to form air turbulence within the condensed chamber. These barriers are generally located within a few thousandths of an inch from the surface of the substrate.

Analysis of drug-containing aerosols
[00109] The purity of a drug-containing aerosol can be determined using a wide variety of methods. the term"
It should be noted that when "purity" is used, it represents the percentage of aerosol minus the percentage of by-products produced during its formation. By-products are, for example, unintended products produced during vaporization. For example, by-products include thermal decomposition products and unintended metabolites of the active compound or compound category. Examples of suitable methods for determining aerosol purity are Sekine et al., Journal of Forensic Science 32: It is described in 1271-1280 (1987) and Martin et al., Journal of Analytic Toxicology 13: 158-162 (1989).

[00110] One suitable method involves the use of traps. In this method, aerosols are collected in traps to determine the percentage or fraction of by-products. Either the appropriate trap can be used. Suitable traps include filters, glass wool, impinger, solvent traps, cooling traps and the like. Filters are often the most desirable. The trap is then generally extracted with a solvent, such as acetonitrile, and the extract is analyzed by any of a variety of analytical methods known in the art, such as particularly useful gas, liquid and high performance liquid chromatography.

[00111] Gas or liquid chromatography methods generally include detection systems such as mass spectrometry detectors or UV absorption detectors. Ideally, the detection system can determine the weight of the components and by-products of the drug composition. It actually measures the signal obtained during the analysis of one or more known mass components (standards) of the drug composition or by-product, and then the signal obtained during the analysis of the aerosol with the standard (s). ) Is compared with the obtained signal, i.e. achieved by a method well known in the art.

[00112] In many cases, the structure of the by-product may not be known or a standard product for it may not be available. In such cases, the weight fraction of the by-product is calculated by assuming that it has the same response coefficient (eg, the same extinction coefficient for UV absorption detection) as the drug component or components in the drug composition. You may. When performing such an analysis, by-products present in less than a very small fraction of the pharmaceutical compound, eg, less than 0.1% or 0.03% of the pharmaceutical compound, are generally excluded. Since it is often necessary to assume that the response of the drug and the by-product is the same when calculating the weight% of the by-product, an analysis method in which such an assumption has a high probability of validity is used. It is often more desirable to use.
In this regard, high performance liquid chromatography with detection by UV absorption at 225 nm is generally desirable. UV absorption at 250 nm for compound detection if the compound absorbs more strongly at 250 nm, or if for other reasons detection at 250 nm is considered by those skilled in the art to be the best means of estimating purity (weight) using HPLC analysis. Can be used. In certain cases where UV drug analysis is not available, purity can be determined using other analytical tools such as GC / MS or LC / MS.

[00113] Changes in the gas under which vaporization of the composition occurs can also affect purity.
Other analytical methods
[00114] The particle size distribution of the drug-containing aerosol can be determined using any suitable method in the art (eg, cascade impaction). The next-generation cascade impactor (MSP Corporation, Shoreview, Minnesota) connected to the vaporizer by an induction port (USP Induction Port, MSP Corporation, Shoreview, Minnesota) is a system used for cascade impact tests. Is.

[00115] The inhalable aerosol mass density can be determined, for example, by delivering the drug-containing aerosol into a limited chamber via an inhalation device and measuring the mass collected in that chamber. Generally, the aerosol is drawn into the chamber due to the pressure gradient between the device and the chamber, at which time the chamber is at a lower pressure than the device. The volume of the chamber should be close to the inhalation volume of the inhaling patient, generally about 2-4 liters.

[00116] Inhalable aerosol The drug mass density can be determined, for example, by delivering the drug-containing aerosol into a limited chamber via an inhalation device and measuring the amount of active pharmaceutical compound collected in that chamber. Generally, the aerosol is drawn into the chamber due to the pressure gradient between the device and the chamber, at which time the chamber is at a lower pressure than the device. The volume of the chamber should be close to the inhalation volume of the inhaling patient, generally about 2-4 liters. The amount of active pharmaceutical compound collected in the chamber is determined by extracting the chamber, performing a chromatographic analysis of the extract, and comparing the results of the chromatographic analysis with that of a standard product containing a known amount of drug. It is determined.

[00117] The concentration of inhalable aerosol particles can be determined, for example, by delivering the aerosol phase drug into a limited chamber via an inhalation device and measuring the number of particles of a particular size collected in the chamber. The number of particles of a particular size can be measured directly based on the light scattering properties of the particles. Alternatively, the number of particles of a particular size can be determined by measuring the mass of the particles within a particular size range and then calculating the number of particles based on that mass according to: Total number of particles = Number of particles in each size range. Sum (from size range 1 to size range N). Number of particles of a particular size = mass in that size range / mass of typical particles in that size range. Mass of typical particles in a particular size range = π ^* D ^{3 *} φ / 6; where D is the diameter (micron) of typical particles in that size range (generally, the average boundary MMAD defines the size range). Yes, φ is the particle density (g / mL) and the mass is expressed in picograms (g- ¹² ).

[00118] The rate of inhalable aerosol particle formation can be determined, for example, by delivering the aerosol phase drug into a limited chamber via an inhalation device. Delivery is for a set period of time (eg, 3 seconds) and the number of particles of a particular size collected in the chamber is determined as outlined above. The particle formation rate is equal to the number of collected 10 nm to 5 micron particles divided by the collection period.

[00119] The rate of aerosol formation can be determined, for example, by delivering the aerosol phase drug into a limited chamber via an inhalation device. Delivery is for a set period of time (eg, 3 seconds) and the mass of the collected granules is determined by weighing the limited chamber before and after delivery of the granules. The aerosol formation rate is equal to the increase in chamber mass divided by the collection period. Alternatively, if the change in mass of the delivery device or its components can only occur due to the release of aerosol phase granules, then the mass of the granules is equal to the mass lost from the device or component during delivery of the aerosol. can do. In this case, the rate of aerosol formation is equal to the mass reduction of the device or component during the delivery event divided by the duration of the delivery event.

[00120] The rate of drug aerosol formation can be determined, for example, by delivering the drug-containing aerosol into a limited chamber over a set period of time (eg, 3 seconds) via an inhalation device. If the aerosol is a pure drug, the amount collected in the chamber is measured as described above. The rate of drug aerosol formation is equal to the amount of drug collected in the chamber divided by the collection period. If the drug-containing aerosol contains a pharmaceutically acceptable excipient, the drug aerosol formation rate is obtained by multiplying the aerosol formation rate by the percentage of the drug in the aerosol.

kit
[00121] In certain aspects of the invention, a kit is provided for use by a healthcare provider, or more preferably a patient. Kits for delivering composition condensed aerosols generally include a composition comprising a drug and a device for forming the condensed aerosol. The composition is generally free of solvents and excipients and generally contains a thermostable drug. Devices for forming a condensed aerosol are generally elements configured to heat the composition to form a vapor, an element capable of condensing the vapor to form a condensed aerosol, and the user can inhale the condensed aerosol. Includes elements to be used. The devices in the kit can further include artifacts such as breath-actuation elements or lockout elements or weighing / logging devices or tapering devices. A representative kit will include a portable aerosol delivery device and at least a single dose.

[00122] In another embodiment, a kit for delivering a drug aerosol is provided, comprising a thin film of the drug composition and a device for partitioning the membrane as a condensed aerosol. The composition may contain a medicinal excipient. Devices for distributing a thin film of a drug composition as a condensed aerosol include an element configured to heat the membrane to form a vapor, and an element for condensing the vapor to form a condensed aerosol.

[00123] In the kit of the present invention, the composition is generally a thin film, generally about 0.5-3.
It is coated on a substrate with a thickness of 0 microns and it is heated by a heat source. The heat source generally achieves a substrate temperature of at least 200 ° C., preferably at least 250 ° C., or more preferably at least 300 ° C. or 350 ° C., within 2 seconds, preferably within 1 second, or more preferably 0.5. Heat is supplied to the substrate at a rate that substantially completely volatilizes the drug composition from the substrate within seconds. In order to prevent drug decomposition, the heat source preferably does not heat the substrate to a temperature higher than 600 ° C. with the drug film on the substrate. More preferably, the heat source does not heat the substrate to temperatures above 500 ° C.

[00124] The kit of the present invention can consist of various combinations of drugs and drug delivery devices. In some embodiments, the device can also supply more than one drug. Other drugs can be administered orally or topically. Generally, instructions for use are included in the kit.

[00125] The term "drug" as used herein is used in humans or animals to prevent, diagnose, treat or cure a disease, reduce pain, or control or ameliorate any physiological or pathological disorder. Means any compound used. Any suitable pharmaceutical compound can be used. Drugs that can be used include, for example, one of the following classes, but are not limited to: anesthetics, anticonvulsants, antidepressants, antidiabetic agents, antidote, antiemetics, antihistamines. , Anti-infective drug, anti-neoplastic drug, anti-Parkinson's disease drug, anti-rheumatic drug, anti-psychiatric drug, anti-anxiety drug, appetite stimulant and suppressor, blood regulator, cardiovascular drug, central nervous system stimulant, Alzheimer Drugs for disease management, drugs for cystic fibrosis management, diagnostics, dietary supplements, drugs for erectile dysfunction, digestive system drugs, hormones, drugs for the treatment of alcohol poisoning, for the treatment of habits Drugs, immunosuppressants, obesity cell stabilizers, migraine preparations, vehicle sickness preparations, drugs for managing multiple sclerosis, muscle relaxants, non-steroidal anti-inflammatory drugs, opioids, other analgesics and stimuli Drugs, ophthalmic agents, osteoporosis agents, prostaglandins, respiratory agents, sedatives and hypnotics, skin and mucous membrane agents, quitting aids, Tourette syndrome agents, urinary tract agents, and dizziness agents.

[00126] In general, when the drug is an anesthetic, it is selected from one of the following compounds: ketamine and lidocaine.
[00127] In general, when a drug is an anticonvulsant, it is selected from one of the following compounds: GABA analog, thiagabin, vigabatrin; barbiturates, eg pentobarbital; benzodiazepines, eg alprazolam, chronazepam; hydranthin. Such as phenytoin; phenyltriazines such as lamotrigine; various anticonvulsants such as carbamazepine, topiramate, valproic acid, and zonisamide.

[00128] In general, when a drug is an antidepressant, it is selected from one of the following compounds: amitriptyline, amoxapine, benmoxin, bupropion, chromipramine, decipramine, dosrepin, doxepin, imipramine, kitanserin, lofepramine, medihoxamine. , Myanserin, Maprotrin, Mitrazapine, Nortriptyline, Protriptyline, Trimipramine, Benrafaxin, Viloxazine, Citalopram, Cochinin, Duroxetin, Fluoxetin, Fluvoxamine, Milnacipran, Nisoxetine, Paroxetine, Leboxetine, , Brophalomine, sericramine, cloboxamine, iproniazide, isocarboxadide, moclobemid, phenylhydrazine, phenergine, selegiline, sibutramine, tranylcipromin, ademethionine, adrafinyl, amesergide, amitriptyline, amplodidone, benactidine, bupropion Metralindol, milnacipran, minapurine, nephazodone, namitriptyline, ritanserin, roxindol, S-adenosylmethionine, escitalopram, tofenacin, trazodone, tryptophan, and zalospyrone.

[00129] In general, when a drug is an antidiabetic drug, it is selected from one of the following compounds: pioglitazone, rosiglitazone, and troglitazone.
[00130] In general, when a drug is an antidote, it is selected from one of the following compounds: edrophonium chloride, flumazenil, deferoxamine, nalmefene, naloxone, and naltrexone.

[00131] In general, when a drug is an antiemetic, it is selected from one of the following compounds: alysapride, ondansetron, benzquinamide, bromopride, buclidine, chlorpromazine, cinnaridine, creboprid, cyclizine, diphenhydramine, diphenidol, dracetron, Droperidol, granisetron, hyostin, lorazepam, dronabinol, metoclopamide, metopimazine, ondansetron, perphenazine, promethazine, prochlorperazine, scopolamine, triethylperazine, trifluoperazine, triflupromazine, trimetbenzamide, tropicetron, Donperidone, and paronosetron.

[00132] In general, when a drug is an antihistamine, it is selected from one of the following compounds: astemizole, azatazine, brompheniramine, carbinoxamine, cetrizine, chlorpheniramine, cinnaridine, clemastine, cyproheptadine, dex. Dexmedetomidine, diphenhydramine, doxylamine, fexofenadine, atarax, loratidine, promethazine, pyriramine, and terphenidine.

[00133] In general, when a drug is an anti-infective drug, it is selected from one of the following compounds: antiviral drugs such as efavirenz; adjunct agents such as Dapson; aminoglycosides. Kinds such as tobramycin; antifungal agents such as fluconazole; antimalaria agents such as kinine; antituberculous agents such as etambitol; β-lactams such as cefmethazole, cepazoline, cephalexin, cefoperazone, cefoxytin, cepacetril, cephaloglycin, cephalolysin; Cephalosporins such as cephalosporins C, cephalotins; cephamycins such as cephamycin A, cephamycin B, and cephamycin C, cephapyrin, cefradine; antibacterial agents such as clofazimine; penicillins such as penicillins Ampicillin, Amoxycillin, Hetacillin, Calfecillin, Calindacillin, Carbenicillin, Amylpenicillin, Azidocillin, benzylpenicillin, Chrometocillin, Croxacillin, Cyclacillin, Methicillin, Nafcillin, 2-Pentenyl Penicillin, Penicillin N, Penicillin V Penicillin S Diphenicillin; Heptylpenicillin; and Methanpenicillin; Kinolones such as cyprofloxacin, clinafoxacin, difloxacin, grepafloxacin, norfloxacin, ofloxacin, temafloxacin; tetracyclins such as doxicillin and oxytetracycline; Disease medications such as linezolide, trimetoprim and sulfamethoxazole.

[00134] In general, when a drug is an anti-neoplastic drug, it is selected from one of the following compounds: dororoxifene, tamoxifen, and toremifene.
[00135] In general, when a drug is an antiparkinsonian, it is selected from one of the following compounds: rotigotine, amantadine, baclofen, viperidene, benztropin, orphenadrin, procyclidine, trihexyl. Phenidil, Levodopa, Calvidopa, Andropinirole, Apomorphine, Benceradide, Bromocriptine, Bujipin, Cabergoline, Eliprodil, Epstastigmin, Ergoline, Galantamine, Razabemid, Lislide, Magindole, Memantin, Mofegirin, Pergolide, Pirivesol pi , Rasagiline,
Remasemide, ropinerol, selegiline, spheramine, terguride, entacapone, and tolcapone.

[00136] In general, when the drug is an anti-rheumatic drug, it is selected from one of the following compounds: diclofenac, hydroxychloroquine and methotrexate.
[00137] In general, when a drug is an antipsychotic, it is selected from one of the following compounds: acetophenazine, alysapride, amysulfride, amoxapine, amperodide, alipyrazole, bemperidol, benzquinamide, bromperidol, bramate , Butacramol, butaperazine, carphenazine, carpipramine, chlorpromazine, chlorprothixen, chlorpromazine, chromacran, clopentixol, crospirazine, clociapine, clozapine, siamemazine, droperidol, fulpentixol, flufenazine, fluspirylene, haloperidol, loxapine , Melperon, mesolidazine, metofenazeto, morindron, olanzapine, penfluridone, periciadine, perphenazine, pimodide, pipameron, piperasetazine, pipotiazine, prochlorperazine, promazine, kethiapine, remoxiprid, risperidone, sertindol, spiperon , Thioridazine, Trifluperidol, Triflupromazine, Trifluoperazine, Ziprasidone, Zotepin, and zuclopenthixol.

[00138] In general, when a drug is an antidepressant, it is selected from one of the following compounds: alprazolam, bromazepam, diazepam, oxazepam, buspirone, hydroxyzine, methaqualone, medetomidin, metmidate, azinazolam, chlordiazepoxide, Clobenzepam, Flurazepam, Lorazepam, Loprazolam, Midazolam, Alpidem, Alceroxlon, Amphenidone, Azacyclonol, Bromisovalum, Captodiamine, Caprid, Calbuchloral, Carbromar, Chloral betaine (chloral beta) , Fresinoxane, ipsapiraone, resopitron, lorazepam, methaqualone, methaqualone, propanolol, tandospirone, trazadon, zopiclone, and zolpidem.

[00139] In general, if the drug is an appetite stimulant, it is dronabinol.
Is.
[00140] In general, when a drug is an appetite suppressant, it is selected from one of the following compounds: fenfluramine, phentermine and sibutramine.

[00141] In general, when the drug is a blood regulator, it is selected from one of the following compounds: cilostazol and dipyridamole.
[00142] In general, when the drug is a cardiovascular drug, it is selected from one of the following compounds: benazepril, captopril, enarapril, quinapril, lamipril, doxazocin, prazosin, chronidine, verapamil, candesartane, ilbesartane, rosartane. , Termisartan, balsartan, disopyramide, flecanide, mexiretin, prokineamide, propaphenone, quinidine, tocainide, amiodarone, dofetilide, ibutylide, adenosine, gemfibrodil, robastatin, acebutalol, atenololol, atenololol , Pindolol, propranolol, sotalol, zirchiazem, nifedipine, verapamil, spironolactone, bumetanide, etaclinic acid, furosemide, tocainide, amiodarone, triamterene, and metrazone.

[00143] In general, when a drug is a central nervous system stimulus, it is selected from one of the following compounds: amphetamine, brucine, caffeine, dexfenfluramine, dextroamphetamine, ephedrine, fenfluramine, Mazindol, methylphenidate, pemoline, amphetamine, sibutramine, and modafinil.

[00144] In general, when a drug is a drug for the management of Alzheimer's disease, it is selected from one of the following compounds: donepezil, galantamine and tacrine.
[00145] In general, when a drug is a drug for the management of cystic fibrosis, it is selected from one of the following compounds: CPX, IBMX, XAC and analogs; 4-phenylbutyric acid; genistein and similar. Isoflavones; as well as milrinone.

[00146] In general, when a drug is a diagnostic agent, it is selected from one of the following compounds: adenosine and aminohippuric acid.
[00147] In general, when a drug is a dietary supplement, it is selected from one of the following compounds: melatonin and vitamin-E.

[00148] In general, when a drug is a drug for erectile dysfunction, it is selected from one of the following compounds: tadalafil, sildenafil, vardenafil, apomorphine, apomorphine diacetate, phentolamine, and yohimbine.

[00149] In general, when the drug is a gastrointestinal drug, it is selected from one of the following compounds: loperamide, atropine, hyoscyamine, famotidine, lansoprazole, omeprazole, and lebeprazole.

[00150] In general, when a drug is a hormone, it is selected from one of the following compounds: testosterone, estradiol, and cortisone.
[00151] In general, when a drug is a drug for the treatment of alcoholism, it is selected from one of the following compounds: naloxone, naltrexone, and disulfiram.

[00152] In general, when a drug is a drug for the treatment of addiction, it is buprenorphine.
[00153] In general, when a drug is an immunosuppressive drug, it is selected from one of the following compounds: mycophenolic acid, cyclosporine, azathioprine, tacrolimus, and rapamycin.

[00154] In general, when a drug is a mast cell stabilizer, it is selected from one of the following compounds: chromolin, pemirolast, and nedocromil.

[00155] In general, when a drug is a drug for migraine, it is selected from one of the following compounds: almotriptan, aperopride, codeine, dihydroergotamine, ergotamine, eletriptan, flovatriptan, isometeptene. , Lidokine, Lislide, Metoclopamide, Naratriptan, Oxycodon, Propoxyphene, Lizatriptan, Sumatriptan, Torphenamic acid, Zolmitriptan, Amitriptyrin, Athenolol, Chronidin, Cipropheptazine, Zyrthiazem, Doxepin, Fluoxetine, Lysylidene Nortriptin, paroxetine, pizotiphen, pizotilin, propanolol, protriptinin, sertalin, timorol, and verapamil.

[00156] In general, when a drug is a vehicle sickness preparation, it is selected from one of the following compounds: diphenhydramine, promethazine, and scopolamine.
[00157] In general, when a drug is a drug for the management of multiple sclerosis, it is selected from one of the following compounds: bencyclane, methylprednisolone, mitoxantrone, and prednisolone.

[00158] In general, when the drug is a muscle relaxant, it is selected from one of the following compounds: baclofen, chlorzoxazone, cyclobenzaprine, methocarbamol, orphenadrine, quinine, and tizanidine.

[00159] In general, when a drug is a non-steroidal anti-inflammatory drug, it is selected from one of the following compounds: asecrophenac, acetaminophen, alminoprofen, amfenac, aminopropyrone, amixetrin, aspirin, Benoxaprofen, bromfenac, bufexamac, carprofen, celecoxib,
Colin, salicylate, cinchophen, symmethacin, clopriac, chrometacin, diclofenac, diflunisar, etdrac, phenoprofen, flurbiprofen, ibuprofen, indomethacin, indomethacin, ketoprofen, ketorolac, madipredon, meclofenac Mate, nabumetone, naproxen, parecoxib, pyroxicum, pilprofen, lofecoxib, sulindac, tolfenamate, tolmethin, and valdecoxib.

[00160] In general, when a drug is an opioid, it is selected from one of the following compounds: alfentanil, allylprozine, alphaprozine, anileridine, benzylmorphine, vegitramide, buprenorphine, butofanol, carbiphen. , Cypramadol, Chronitazen, Codein, Dextromoramide, Dextropropoxyphene, Diamorphine, Dihydrocodein, Diphenoxylate, Dipipanone, Fentanyl, Hydromorphon, L-alpha Acetylmetadole, Lofentanyl, Levorfanol, Meperidine, Mesadone, Meptadinol , Metopon, morphine, nalbufin, narolfin, oxycodon, papaveretum, pethidine, pentazocin, phenazocin, remifentanyl, spentanyl, and tramadol.

[00161] In general, when the drug is another analgesic, it is selected from one of the following compounds: apazone, benzpiperilone, benzidramine, caffeine, chronixin, etoheptazine, flupertin, nefopam, orphenadrine, propa Setamol, and propoxyphene.

[00162] In general, when the drug is an ophthalmic preparation, it is selected from one of the following compounds: ketotifen and betaxolol.
[00163] In general, when the drug is an osteoporosis preparation, it is selected from one of the following compounds: alendronate, estradiol, estroptate, lysedronate and raloxifene.

[00164] In general, when a drug is a prostaglandin, it is selected from one of the following compounds: epoprostanol, dinoproston, misoprostol, and alprostadil.

[00165] In general, when the drug is a respiratory drug, it is selected from one of the following compounds: albuterol, ephedrine, epinephrine, homoterol, metaproterenol, terbutaline, budesonide, ciclesonide, dexamethasone. , Fluticasone, fluticasone propionate, triamsinolone acetonide, ipratopium bromide, pseudoephedrine, theophylline, montelukast, zafirlukast, ambirlukast, ambricentan, bosentan, enlacentan, citaxcentan, tezocentan, enlacentan, citaxcentan, tezocentan.

[00166] In general, when a drug is a sedative and hypnotic, it is selected from one of the following compounds: butalbital, chlordiazepoxide, diazepam, estazolam, flunitrazepam, flurazepam, lorazepam, midazolam, temazepam, triazolam, zaleplone. , Zolpidem, and Zopiclone.

[00167] In general, when the drug is a skin and mucosal drug, it is selected from one of the following compounds: isotretinoin, bergapten and methoxsalen.

[00168] In general, when a drug is a smoking cessation aid, it is selected from one of the following compounds: nicotine, nicotine meta-salicylate and varenicline.

[00169] In general, when a drug is a Rett Syndrome drug, it is pimozide.
[00170] In general, when the drug is a urethral drug, it is selected from one of the following compounds: torteridine, dalifenicin, propantheline bromide, and oxybutynin.

[00171] In general, when the drug is a vertigo drug, it is selected from one of the following compounds: betahistine and meclizine.
[00172] In general, the inventors have found that suitable drugs have properties that make them acceptable candidates for use in the devices and methods described herein. For example, pharmaceutical compounds are generally volatile or can be volatile. In general, the drug is a thermostable drug. Typical drugs include: acebutrol, acetaminophen, alprazolam, amantazine, amitriptilin, apomorphine diacetate, apomorphine hydrochloride, atropin, azatazine, betahistin, brompheniramine, bumethanide, buprenorfin, bupropion hydrochloride, butarbital, Butofanol, carbinoxamine maleate, selecoxib, chlordiazepoxide, chlorpheniramine, chlorzoxazone, cyclesonide, citaloplum, chromipramine, chronazepam, clozapine, codeine, cyclobenzaprine, cypropheptazine, codeine, cyclobenzaprine, cypropheptazine, dapsone, diazepam, diclosepamine Efedrin, estazolam, etacrinic acid, fenfluramine, phenoprofen, flecainide, flunitracepam, galantamine, granisetron, haloperidol, hydromorphone, hydroxychloroquine, ibuprofen, imiplamine, indomethacin ethyl ester, indomethacin methyl ester, isocarboxazid (isocarboxazid), ketoprofen, ketoprofen, ketoprofen ethyl ester, ketoprofen methyl ester, ketorolac ethyl ester, ketorolac methyl ester, ketotiphen, lamotrigin, lidocain, loperamid, loratazine, loxapine, maprothyrin, memantin, meperidine, metaproterenol Mexiretin HCl, midazolam, mirtazapine, morphine, nalbufin, naloxone, naproxene, nalatryptane, nortryptyrin, olanzapine, orphenadrin, oxycodon, paroxetine, pergolide, phenitoin, pindrol, piribezil, pramipexol, procainide Pyriramine, ketoapine, quinidine, lizatryptane, ropinilol, sertalin, selegiline, sildenafil, spironolactone, taclin, tadalafil, terbutalin, testosterone, salidamide, theophylline, tocainide, tremiphen, trazodon, triazolam, trifluoperacin, valproic acid Vitamin E, Zarepron, Zetepine, Amoxapine, Athenolol , Benztropin, caffeine, doxylamine, estradiol 17-acetate, flurazepam, flurubiprofen, hydroxydine, ibutylide, indomethacin norcholine ester, ketrolacnorcholine ester, melatonin, methoclopamide, nabumetone, perphenazine, protryptyrin HCl, Kinine, Triamterene, Trimipramine, Zonisamide, Bergaptene, Chlorpromazine, Corhitin, Zyrthiazem, Donepezil, Eletriptan, Estradiol-3,17-Diacetate, Efabilens, Esmorol, Fentanyl, Flunisolid, Fluoxetine, Hyostiamine, Indomethacin, Isotre Mecridin, paracoxib, pioglycazone, lofecoxib, sumatriptan, tortellodin, tramadol, tranylcibromin, trimipramine maleate, valdecoxyb, valdenafil, verapamil, solmitriptan, solpidem, zopiclone, bromazepam, buspirone, zopiclone, bromazepam Termisartan, temazepam, albuterol, apomorphine diacetate hydrochloride, carbinoxamine, clonidine, diphenhydramine, thambutol, fluticazone propionate, fluconazole,
Lovastatin, N, O-diacetyllorazepam, mesadone, nefazodone, oxybutynin, promazine, promethazine, sibutramine, tamoxyphene, tolfenamic acid, alipyrazole, astemizole, benazepril, clemastine, estradiol 17-heptanoate, fluphenazine, protryptyrin, etanbutal ), Flovatryptane, pyriramine maleate, scopolamine, and triamsinolone acetonide, and their pharmaceutically acceptable analogs and equivalents.

[00173] The categorized list of drugs specifies that the drug is not limited to one category for another use in another category or new category.

[00174] The pharmaceutically acceptable excipient may be volatile or non-volatile. When heated, the volatile excipient volatilizes at the same time as the drug to be delivered, becomes an aerosol and is inhaled. Classes of such excipients are known in the art and include, but are not limited to, gaseous, supercritical liquid, liquid and solid solvents. The following is a list of representative carriers in these classes: water; terpenes such as menthol; alcohols such as ethanol, propylene glycol, glycerol and other similar alcohols; dimethylformamide; dimethylacetamide; wax; And its mixture.

[00175] The present disclosure teaches the use of antistatic agents in airways for thermal aerosol generation devices for drugs that are prone to charge during aerosol generation. These include, but are not limited to, the drugs listed above.

[00176] The various aspects of the present disclosure are the various elements of the claims, as if the dependent claims were multiple dependent claims, including the limitations of the preceding dependent claim and the independent claim, respectively. It can also include replacement. Such replacement is clearly within the scope of this disclosure.

[00177] Although the present invention has been presented and described in particular with respect to a number of aspects, the various aspects disclosed may be modified in form and detail without departing from the spirit and scope of the invention, as well as herein. It will be appreciated by those skilled in the art that the various aspects disclosed in the above are not intended to be used as a limitation of the scope of claims. All references cited herein are incorporated herein by reference in their entirety.

Example 1: Electrostatic phenomenon in a heat-condensed aerosol
[00178] Here we provide an elucidation of the electrical properties of heat-condensed aerosols of a number of drugs in the Staccato® system.

Method
[00179] Test formulations and devices
[00180] Several benzodiazepine drugs (alprazolam, estazolam, triazolam, diazepam, clobazam), loxapine, prochlorperazine, and zarepron. (zaleplon) was used on the Staccato single dose platform. The Staccato single dose platform is an inspiratory actuation and consists of a thin film of excipient-free drug coated on a stainless steel substrate inside a plastic airway housing. As the patient inhales through the device, the substrate becomes hot due to the internal energy source. The drug membrane evaporates rapidly, accompanies the air stream inside the airway housing, and finally condenses into an aerosol (Fig. 1).

[00181] The vapor phase drug cools almost instantly in an air stream, condensing the drug into aerosol particles of 1-3 μm. See FIG.
[00182] Drug formulation: alprazolam, estazolam, triazolam, diazepam,
Clobazam, loxapine, prochlorperazine, and zaleplon.

[00183] A free base drug dissolved in an appropriate solvent was spray-coated on a substrate with a film thickness of 3 to 8 μm.
Electrometer: The TSI model 3068A aerosol electrometer measures the total net charge on the aerosol drug particles.

[00185] ESD Simulator: Schaffner Model NSG 435 ESD
Simulator; Induces a specific polarization and amount of potential into a plastic airway housing.

[00186] Procedure: Experiment 1a: Measurement of net charge
[00187] The total net charge of the aerosol particles was measured with an aerosol electrometer (TSI3068A). The sample flow rate was set to 10 LPM; because it was the upper limit of the aerosol.

[00188] Electrometer. The device was manually activated to cause device activation, heating and vaporization of the drug membrane, followed by condensation of the drug into aerosol particles. An electrometer was connected to the oscilloscope to capture the current output of the aerosol. The total net charge of the aerosol was calculated by integrating the current-pair-time curve from the oscilloscope and dividing by the total drug mass released from the device. At least two equivalent tests were performed for each drug.

[00189] Experiment 1b: Effect of induced charging on airway housing deposition
[00190] A filter holder containing a glass fiber filter (Whatman) (
By connecting the Pall in-line filter holder) to the vacuum pump, aerosol deposition on the airway housing was measured. The air flow rate was set to 15 LPM for 5 seconds. When the setup was complete, an ESD simulator was used to apply a potential of either + 16 kV or -16 kV to the plastic airway housing. Air flow was initiated by switching on the solenoid valve to activate the device. After operation of the device, the Staccato device was opened and the airway housing was assayed by extraction and high performance liquid chromatography analysis to determine aerosol deposition. Unless otherwise stated, each drug was subjected to at least 3 equivalent tests.

Experiment 2: Total net charge-vs.-Airway housing deposition: Total net charge (part la) and housing deposition were measured simultaneously for Staccato alprazolam. Two Staccato alprazolam device versions were tested in this part of the test. The first version (used in Part 1) used an airway housing made of polycarbonate with a surface resistivity of −l × 10 ¹⁸⁰ / sq. The second version, in order to produce a charge dissipation (charge dissipation), was used airway housing created in a lower resistivity polycarbonate ^{(-1 × 10 11 0 / sq} ).

[00191] Results and discussion
[00192] Most heat-condensed drug aerosols did not show high charge content. However, the total net charge of the aerosol particles for certain structurally similar benzodiazepines (alprazolam, estazolam and triazolam) was substantial (Table 1).

[00193] Induced charging on the housing by the applied electric field amplifies the effects of electrostatic interactions and aerosol deposition on the housing components. Table 1 shows the results of aerosol deposition on the airway housing for alprazolam, prochlorperazine, and loxapine. Overall, induced charging on the housing was shown to have minimal effect on the aerosol of prochlorperazine or loxapine. No tests were conducted with an electric field applied, but the airway housing deposition shown by Zaleplon was negligible. For alprazolam aerosols, airway housing deposition increased significantly when the housing was positively charged, suggesting that the alprazolam aerosol is negatively charged. This finding is consistent with the net charge result for alprazolam aerosol from part la. The charging process appears to result from the triboelectric separation of different substances (organic drugs and steel substrates). It is not clear why this happens for certain benzodiazepines, such as alprazolam, estazolam, and triazolam, but not for other drugs, but the molecular structures of alprazolam, estazolam, and triazolam, as well as additional free electrons. It seems to be a function of their stability in delocalization.

Table 1
Net charge and aerosol deposition on the housing (mean ± SD)
[00194]

Previous studies have shown that a conductive surfactant coating on the surface of device components is effective in dissipating charges [9-10]. Here, in order to reduce airway housing deposition and emission loss, antistatic polycarbonate, which has significantly lower electrical resistance than standard polycarbonate, was used for the Staccato alprazolam. The total net charge of the alprazolam particles and the airway housing deposition were measured for the standard Staccato alprazolam device and the Staccato alprazolam device using the antistatic housing material. The results are shown in Table 2. The total net charge on the alprazolam particles released from the antistatic housing was 100-fold less than that from the standard housing, while aerosol deposition on the airway housing was also significantly reduced in the antistatic housing.

[00196] The electrostatic phenomena in the heat-condensed aerosols of several benzodiazepines (alprazolam, estazolam, triazolam, diazepam, clobazam), prochlorperazine, loxapine, and zaleplon were investigated. Alprazolam aerosols exhibit a relatively large net negative charge, which can result in substantially higher aerosol deposition on the airway housing. To overcome the electrostatic interaction, polycarbonate with higher conductivity was used for the housing. This significantly reduced the total net charge of the alprazolam aerosol and the deposition of the airway housing.

Example 2:
[00197] Aerosol charging tests on heat packages and screening foils using an aerosol electrometer. For screening foils, aerosol charging had a small positive electrode property and was not associated with coating density. For the Staccato heat package, the aerosol charge was large and negative when the Statice was not used, while the aerosol charge was small and negative when the Staticide was used. Bumetanide and PCZ aerosols were negatively charged aerosols about an order of magnitude lower than alprazolam.

Example 3:
[00198] Aerosol charging test using a heat package and a funnel as an access path to an aerosol electrometer. The heat package was operated without a housing. Negative charges were generated using galvanized steel braces. A positive charge was generated using a plastic wax. Additional tests have shown that partially statice coated airways generate positive alprazolam aerosols. Other tests have shown that Zarepron devices have a low charge.

Example 4:
[00199] Aerosol charging test using Permasat and Permasat plus airways. Airways made of Permastat and Permastat plus conductive polycarbonate alloys showed a significantly significant reduction in aerosol charging and airway deposition when compared to standard airway materials.

Example 5:
[00200] Aerosol charging test using a screening foil device modified to apply an electrostatic field to the screening foil during vaporization. This experiment showed that the aerosol charge increased monotonically with the strength of the applied potential difference. However, the potential difference used (0V-5kV) caused saturation of the electrometer sensor.

Example 6:
[00201] Follow-up aerosol charging test using a screening foil device modified to apply an electrostatic field to the screening foil during vaporization. The voltage range applied in this experimental setting was 0V to 500V because it saturates at the higher voltage. In this case as well, there was a monotonous tendency for the increase in aerosol charge as the electric field strength increased.

Example 7:
[00202] Aerosol charging test using a metallized housing to apply an electrostatic field to the heat package during vaporization.

[00203] Phase 2 A2 DCT2 aerosol property test at 28.3 LPM (P)
With SD, ED, and EP, 0.5 mg ALP). An electrostatic test was performed on ALP using this DCT. Higher airway deposition (crystallization) was seen from devices tested 4 days later rather than on the day of drug coating (amorphous). Drug crystals were found on both HP and the airway (first of these) after activating the device that had been coated for 4 days.

Example 8:
[00204] HP type (one-sided-vs-two-sided) and coating spray rate testing.
Phase 2 A2 DCT2 ED and EP, at 28.3 LPM (1.5 mg). Original coating parameters were tested on both unilateral and bilateral HPs and drug crystals were found on the airways for both types of HPs. A lower spray rate was given, but drug crystals were still found on the airway. The presence of drug crystals on the airway was not caused by unilateral or bilateral HP or lower spray rates.

Example 9:
[00205] Coating spray rate. Phase 2A2 with lower spray rate
DCT2 ED, 28.3 LPM (0.5 mg). The average airway deposition was 10%. After activation, drug crystals were present on all airways. Again, lower spray velocities did not solve the airway deposition problem.

Example 10:
[00206] High-to-cold HP at lower spray rates. Phase 2 A2 DCT2
, ED and EP, 28.3 LPM, 1.5 mg. Cold HP visually and quantitatively had fewer drug crystals on the airway.

Example 11:
[00207] Airway deposition inspection using HP, PNF0027, 1 mg from lot M0167. Low airway deposition when the device was held without gloves (no crystals), but high when held with gloves (with drug crystals).

Example 12:
[00208] Airway deposition tests for the following effects: 1) HP with and without gloves for HP with 1 and 2 passes coating, and 2) ESD gun (8 kV +) , 8kV-, 16kV +). Airway deposition was higher with gloves and higher with increasing positive electrodeposition of the ESD gun (highest at 16 kV +, lowest at 8 kV-). This also suggested that the ALP aerosol was net negatively charged.

Example 13:
[00209] Effect of 16kV +, 16kV- and ground contact conditions on clamshell and front / back airway deposition. The results showed that the clamshell airway had the highest airway deposition at 16 kV +, followed by the ground airway, which was minimal when 16 kV- was applied. A similar trend was seen on the front / back airways, but with less deposition.

Example 14:
[00210] Effect of 16 kV + and 16 kV- on PCZ and loxapine. The results showed that there was no significant effect on airway deposition from +/- 16 kV.

[00211] The effect of gloves on airway deposition of PCZ and loxapine, and the effect of +/- 16 kV and ground contact conditions on ALP airway deposition. Gloves had no effect on airway deposition of PCZ and loxapine. 16kV + still produced the highest ALP airway deposition, and the ground contact conditions showed about the same amount of ALP airway deposition as 16kV-, but less than 16kV +. The test also showed that a large amount of ALP airway deposition was seen for the amorphous coating.

Example 15:
[00212] Comparison of ALP airway deposition in grounded and non-grounded conditions in high and low humidity environments. This test showed that airway deposition was significantly higher at low humidity (20% RH) compared to 40% RH. However, this test showed no significant difference between grounded and non-grounded conditions under both humidity settings.

[00213] Comparison of ALP airway deposition with and without grounding a person in two different humidity conditions (28 and 55% RH), and varying from the device in the foil pouch to the moment of operation. Measurement of electric charge using an electrometer at the stage of. The results showed that airway deposition at 28% RH was generally higher than at 55% RH. By grounding the person holding the device, airway deposition was reduced in most cases. The electrometer test shows that 1) some static charge is already present on the foil pouch, 2) the static charge on the airway increases after removing the pull tab in most cases, and 3). It has been shown that grounding a person during operation reduces the static charge on the airway.

Example 16:
[00214] ALP airway deposition test using antistatic spray and copper tape. This test showed that both antistatic spray and copper tape can reduce airway deposition even when 16 kV + is applied to the airway.

[00215] AL using antistatic spray and copper tape at low humidity (27% RH)
P airway deposition test. This test showed that antistatic sprays and copper tapes help reduce airway deposition, even in low humidity conditions.

[00216] ALP airway deposition test using antistatic spray when HP has normal reactant propagation time (previous test 152p144-151 used HP with slower propagation time). ). The results also showed that the antistatic spray reduced airway deposition regardless of the reactant propagation time.

Example 17:
[00217] ALP airway deposition test comparing external actuation (with actuation box) and pull tab actuation; at which time 1) 16 kV + was applied to the airway, 2) the airway was held without gloves, and 3) the airway was grounded. .. The results showed that there was no difference in airway deposition between pull-tab actuation and external actuation under the three conditions tested. Deposits were not reduced.

Example 18:
[00218] ALP airway deposition test; at that time, 1) the airway was pre-cleaned with IPA before the test, and 2) the airway was constructed without a check valve. The results showed that neither case reduced airway deposition.

Example 19:
[00219] ALP airway deposition test in which the device was constructed by a manufacturing group and tested with one-sided HP (front / back airway) and two-sided HP (clamshell airway) without gloves. The results showed that one-sided HP had higher airway deposits (16%), while bilateral HPs had lower airway deposits (2%).

Example 20
[00220] ALP airway deposition test in which the device was constructed by a manufacturing group and 16 kV + was applied to the airway. One-sided HP (front / back airway) and both-sided HP (clamshell airway) were tested. The results showed that one-sided HP (17%) had higher airway deposits than bilateral (1%).

Example 21
[00221] ALP airway deposition between manufacturing groups and devices constructed by R & D (Jasmine) was compared to identify a series of assembly differences between the two. 16 kV + was applied to the airway. The results showed that the devices built by the manufacturing group had lower airway deposition.

Example 22
[00222] Comparison of ALP airway deposition between pouched and pouched devices (devices removed from foil pouch 20 hours before testing). 16 kV + was applied to the airway. The results showed that there was no significant difference in airway deposition between these two conditions.

Example 24
[00223] Comparison of ALP airway deposition for the effects of +/- 16 kV. These devices were built by the manufacturing group. The results showed that both conditions had little effect on airway deposition.

Example 25
[00224] All devices built and pouched by the manufacturing group, AL
P airway deposition test. The QC group tested both control (normal) and statice devices without applying 16 kV +. The R & D group tested both control (normal) and statice devices with 16 kV + applied to the airway. These were tested for 16 days. The results showed that there was more airway deposition on the control (normal) device than that of statice. All static devices from both the QC and R & D groups had very low airway deposits. Control (normal) devices had more airway deposits when tested by R & D compared to QC.

Example 26
[00225] ALP airway deposition test in which + 16 kV was applied during the manufacture of the assembled device (first batch). Very little airway deposits were seen.

Example 27
[00226] HP is DCM A instead of methanol / acetone 50/50 ALP solution
ALP airway deposition test coated with LP solution. The results showed that the DCM coating solution did not help reduce airway deposition.

Example 28
[00227] ALP airway deposition test using an ionizer. The results showed that the ionizer reduced airway deposition.

Example 29
[00228] Airway deposition tests for ALP, PCZ, and loxapine at 10 LPM. For ALP, the results show that statice devices have low airway deposition, while normal (control) devices constructed by R & D have high airway deposition, while those constructed by the manufacturing group have slightly lower airway deposition. It was. PCZ had very few airway deposits, while loxapine had a large amount of airway deposits.

Example 30
[00229] ALP airway deposition test in which the device was placed in a pouch for different days and different humidity. The results showed that there are some devices with higher airway deposits, although airway deposits generally do not change much.

Example 31
HP surface and aerosol charge measurements; 1) normal / control airways containing ALP, 2) statice airways containing ALP, 3) normal / control airways (placebo), and 4) statice airways (placebo). The results showed that normal airways containing ALP had the highest aerosol charge, while others had very low charges and were all negative polarities. HP surface charge was positive on all normal airways. On the statice airway, HP charges appeared to have higher variability, with positive, zero, and negative charges measured. It was also found that the deposit amount on the statice airway was almost 0%.

Example 32
[00231] Aerosol charging and airway deposition tests using normal (control), metallized, and Permasat plus airways. For normal airways, both aerosol charging and airway deposition were high. For metallized airways, aerosol charging was mostly high, but airway deposition was low. For the Permasat plus airway, both aerosol charging and airway deposition were low.

Example 33
[00232] Aerosol property test using Permasat airway at 28.3 LPM. ED, PSD, and EP were all good and within expectations. It was found that there was almost no deposition on the airway.

Example 34
[00233] Aerosol charging and airway deposition using Permasat airways with different surface resistances. Airway deposits were negligible in all cases. The aerosol charge was low, but most of them had a positive charge rather than a negative charge.

Example 35
[00234] Aerosol charging and airway deposition using Permasat airways and conventional airways (continuation of previous test A233p110-p115). This test further confirmed that airway deposition was negligible for Permasat airways and that aerosol charges were low for both the measured positive and negative charges. Normal airways assembled by the manufacturing group have lower airway deposits and lower charges (positive and negative charges), while those assembled by R & D have higher airway deposits and much higher aerosol charges (positive and negative charges). There was a negative charge).

Example 36
[00235] Acetone-bonded ordinary airway and THF-bonded Perm
Comparison of EP with astatine airway. The results showed that there was no difference in EP.

Example 37
Leakage and tensile tests using Loctite-bonded Permastat airways and acetone-bonded normal (control) airways. Leakage rates were good for both airways. The force required to pull the Permasat airway apart was less than that of a normal airway.

Example 38
[00237]
I. Airway deposition and aerosol charging for Permasat, Permastat Plus, and standard airway materials (# 3)
Purpose:
To elucidate the aerosol charge generated from the Permastat and Permasat Plus airways and compare it with the normal airway (control).
Material / Equipment ○ Standard airway material: macron polycarbonate ○ Permasat: Surface resistivity Approx. 1E11 ohm / sq
○ Permasat Plus: Surface resistivity of about 1E9 ohm / sq
○ Drug: Alprazolam
Experimental settings ● A single dose Staccato alprazolam device was placed on a mouthpiece connected to an aerosol electrometer;
● The aerosol generated at 28.3 LPM was captured in an aerosol electrometer and measured for current (pA);
● The measured current was recorded on a computer and the charge was calculated by integrating the current-time graph;
● The housing was extracted with solvent and the amount of drug was determined using HPLC.

[00238] Table 3

Results: See Table 3 and Figure 2.
[00240] CONCLUSION: For Permasat and Permasat Plus airways, aerosol charging and airway deposition were significantly reduced.

Example 39
II. ESD simulator with antistatic spray and copper tape or alprazolam airway deposition in low humidity (# 18 and 19)
Purpose:
Determining how to reduce airway deposits
Materials / Equipment ○ General purpous statice Coated airway: General purpous inside and outside the airway
Sprayed polycarbonate ○ Heavy duty statice Coated airway: Sprayed on the inside and outside of the airway ○ Conductive / copper airway: Copper tape was attached to the inside and outside of the airway Things ○ Ordinary airway or control: Makerlon
○ ESD simulator ○ Drug: Alprazolam
Experimental settings A. Airway deposition at ambient humidity (approx. 41% RH-54% RH) ● Apply + 16kV to the airway using an ESD simulator to charge the drug-side airway ● Aerosol generation at 15 LPM for devices with various airways: general copper statice Coated airways, heavy duty statice coated airways, and conductive / copper airways ● Extract the airways with a solvent to determine the amount of drug deposited on the airways. Airway deposition at low humidity (approx. 27% RH) ● Aerosol generation at 15 LPM for devices with various airways: general purpose statice coated airways, conductive / copper airways, and ordinary airways ● Extract airways with solvent and use them in airways Determine the amount of deposited drug Results A. Airway deposition at ambient humidity (approximately 41% RH-54% RH) B. Airway deposition at low humidity (about 27% RH)

[00241] Table 4
[00242] Both statice and copper tape can substantially reduce airway deposition under either ambient or low humidity conditions.

Example 40
III. Airway deposition and aerosol charging of various airways (# 35)
Objective To compare airway charging and aerosol deposition of various airways: normal airways, metallized airways (SS ^* / Cu / Cu / SS), and Permasat Plus airways.
Material / Equipment ○ Standard airway material: Macintosh Polycarbonate ○ Metallized airway: Stainless steel / copper / copper / stainless steel layer coated on the inside of the housing ○ Permasat Plus: Surface resistivity of about 1E9 ohm / sq
Experimental settings ● A single dose Staccato device was placed on a mouthpiece connected to an aerosol electrometer;
● For tests with 16 kV + applied, electrostatic gun (ESD)
The airway was charged using a simulator);
● The aerosol generated at 28.3 LPM was captured in an aerosol electrometer and measured for current (pA);
● The measured current was recorded by a Tektronix scope and transmitted to a computer;
● The charge was calculated by integrating the current-time graph;
● Airways and HP were extracted for quantitative analysis (inspecting deposits);

[00243] Metallized airways did not reduce aerosol charge, but reduced airway deposition, while Permasat Plus airways reduced both aerosol charge and airway deposition.

Example 41
IV. Aerosol characteristics using Permasat airway (# 36)
Objective To evaluate aerosol properties using the Permastat airway.
Materials / Equipment ○ Staccato alprazolam device constructed with Permastat housing ○ Staccato alprazolam device constructed with ordinary polycarbonate housing
Experimental settings ● Flow velocity = 28.3 LPM
● Emitted dose, particle size, and emitted purity were collected for Permasat housings and ordinary polycarbonate housings.

[00244] See FIG.
[00245] The emission amount, particle size, and emission purity using the Permastat airway were good and within the expected range. The deposition seen on the Permasat airway was almost zero.

Example 42
I. Net charge for various drugs and aerosol deposition on airways (quoted from numerous studies)
Several benzodiazepines (alprazolam, estazolam, triazolam, diazepam, clobazam), loxapine, prochlorperazine, and zaleplon were used on the Staccato single dose platform. The airway was charged using an electrostatic gun (ESD simulator) to amplify the effect of the electrostatic effect.

Those skilled in the art will appreciate that the experimental device detailed above can be converted to an inhalation delivery device by removing the sealed vial and including a housing containing the assembly and electrical elements. The housing will accommodate the air inlet and mouthpiece, thus carrying the aerosol formed when the drug volatilizes into the subject's lungs.

The present invention also includes the following aspects.
Aspect 1
A device for delivering a condensed aerosol, including a housing and an airway, wherein the airway housing contains an antistatic material.
Aspect 2
The device according to aspect 1, wherein the antistatic material is coated on the inner wall of the airway.
Aspect 3
The device according to aspect 2, wherein the antistatic material constitutes a metallized airway, wherein the inner wall of the airway is coated with a conductive metal.
Aspect 4
The device according to aspect 3, wherein the conductive metal comprises stainless steel / copper / copper / stainless steel.
Aspect 5
The device according to aspect 1, wherein the antistatic material comprises a metal tape applied to the inner and outer walls of the airway.
Aspect 6
The device of aspect 1, wherein the antistatic material comprises an antistatic spray applied to a default airway.
Aspect 7
The device according to aspect 1, wherein the antistatic material is composed of an antistatic plastic applied as an airway material.
Aspect 8
The device according to aspect 1, wherein the condensed aerosol comprises a drug that is prone to charge upon generation of the aerosol.
Aspect 9
8. The device of aspect 8, wherein the drug is alprazolam.
Aspect 10
A method of producing a drug-condensing aerosol to a patient by inhalation in a drug delivery device, in which a thin layer containing the drug on a solid support is heated to generate a drug vapor, which is condensed to 10 weight. A method in which the airway of a drug delivery device comprises an antistatic material by forming a condensed aerosol by forming a condensed aerosol characterized by less than% drug degradation product and less than 5 micron MMAD.
Aspect 11
10. The method of aspect 10, wherein the antistatic material is coated on the inner wall of the airway.
Aspect 12
10. The method of aspect 10, wherein the antistatic material constitutes the metallized airway, wherein the inner wall of the airway is coated with a conductive metal.
Aspect 13
12. The method of aspect 12, wherein the conductive metal comprises stainless steel / copper / copper / stainless steel.
Aspect 14
10. The method of aspect 10, wherein the antistatic material is composed of metal tape applied to the inner and outer walls of the airway.
Aspect 15
10. The method of aspect 10, wherein the antistatic material comprises an antistatic spray applied to the default airway.
Aspect 16
10. The method of aspect 10, wherein the antistatic material is composed of an antistatic plastic applied as an airway material.
[00247] The above description of a particular aspect of the invention is presented for illustration and description. It should be understood that they are not exhaustive or are not intended to limit the invention to the exact form disclosed, and that numerous modifications and modifications are possible in light of the above teachings. .. Those embodiments best describe the principles of the invention and its practical application, thereby being modified by others skilled in the art to suit the particular use intended for the present invention and various aspects. Selected and described for good use. Many other modifications are also considered to be within the scope of the present invention.

Claims (16)

A device for delivering a condensed aerosol, including a housing and an airway, wherein the airway housing contains an antistatic material. The device of claim 1, wherein an antistatic material is coated on the inner wall of the airway. The device of claim 2, wherein the antistatic material constitutes a metallized airway, wherein the inner wall of the airway is coated with a conductive metal. The device of claim 3, wherein the conductive metal comprises stainless steel / copper / copper / stainless steel. The device of claim 1, wherein the antistatic material comprises a metal tape applied to the inner and outer walls of the airway. The device of claim 1, wherein the antistatic material comprises an antistatic spray applied to the default airway. The device according to claim 1, wherein the antistatic material is made of an antistatic plastic applied as an airway material. The device of claim 1, wherein the condensed aerosol comprises a drug that is prone to charge upon generation of the aerosol. The device of claim 8, wherein the drug is alprazolam. A method of producing a drug-condensing aerosol to a patient by inhalation in a drug delivery device, in which a thin layer containing the drug on a solid support is heated to generate a drug vapor, which is condensed to 10 weight. A method in which the airway of a drug delivery device comprises an antistatic material by forming a condensed aerosol by forming a condensed aerosol characterized by less than% drug degradation product and less than 5 micron MMAD. The method of claim 10, wherein the antistatic material is coated on the inner wall of the airway. The method of claim 10, wherein the antistatic material constitutes the metallized airway, wherein the inner wall of the airway is coated with a conductive metal. 12. The method of claim 12, wherein the conductive metal comprises stainless steel / copper / copper / stainless steel. 10. The method of claim 10, wherein the antistatic material comprises metal tape applied to the inner and outer walls of the airway. The method of claim 10, wherein the antistatic material comprises an antistatic spray applied to the default airway. The method of claim 10, wherein the antistatic material is composed of an antistatic plastic applied as an airway material.